Human NK cell functions in immunity and reproduction are controlled by highly polymorphic interactions between killer cell immunoglobulin-like receptors (KIR) and major histocompatibility complex (MHC) I ligands. In aggregate these interactions individualize human immune systems and individually they correlate with disease susceptibilities and outcome of clinical transplantation. The rapidity with which MHC class I and KIR evolve is such that only the higher non-human primates (apes and monkeys) have equivalents to the human components and thus these species provide the most valid animal models. Chimpanzees have proved informative, because their MHC is very similar to the HLA region, the observed differences being likely to contribute to their relative resistance to certain human infections. Although chimpanzees are overall more genetically diverse than humans, Patr-A is less polymorphic than HLA-A, and lacks an equivalent of HLA-A*02, the most common human allotype. In this context we studied Patr-AL, a novel and chimpanzee-specific MHC class I that is encoded by a novel, non- polymorphic gene, with distinctive tissue distribution, and a peptide- binding specificity like HLA-A*02. In Aim 1 crystallography of Patr-AL will be undertaken to determine if this common specificity is the result of convergent or divergent evolution. A candidate human AL gene has been identified and associated with HLA haplotypes from non-caucasoid populations. The location of this gene in the MHC will be determined, and the function of its encoded protein assessed. Whereas many chimpanzee Patr-B allotypes carry the C1 epitope recognized by KIR2DL2/3, this lineage of B allotypes is represented in humans by a single poorly characterized allotype, HLA-B*7301, that is widely dispersed, but resistant to the recombination that marks HLA-B. We propose in Aim 2 to study the functional role of B*7301 as a ligand for KIR. Through analysis of B*73 in populations and the B*73 counterparts in apes, we will reconstruct the human history of HLA-B*7301. Orangutans have proved informative because the interactions between MHC-C and KIR that dominate the humans system, is simpler and resembles an intermediate stage of construction. In Aim 3 we will test the hypothesis that interactions between MHC-A and MHC-B and KIR are more dominant in the regulation of orangutan NK cells than in humans. As has repeatedly been demonstrated by the prior achievements of this research program, these studies will provide valuable new insights and perspective to the workings of the human immune system that could never be obtained from studying either humans alone or mouse models. PUBLIC HEALTH RELEVANCE: Natural killer cells are a population of lymphocytes that makes essential contributions to immune defense and placental reproduction. These functions are controlled by diverse interactions between polymorphic killer cell immunoglobulin receptors (KIR) and major histocompatibility complex (MHC) class I ligands. By studying these rapidly evolving immune system components in closely related species of non-human primate we will gain new insight and greater understanding of the human system and its contribution to human health and survival.